Cytotoxic Drugs and the Granulopoietic System

Lohrmann, Hans‐Peter; Schreml, W.

doi:10.1007/978-3-642-81690-1

Cited by 37 publications

(27 citation statements)

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“…We have modeled this process by drug compartments 4 and 5 ( Figure 1), which represent free and bound drug, respectively. In this way we could achieve a prolonged effect of doxorubicin, long after it disappears from the blood, in accordance with experimental results [15]. The equations of doxorubicin PK/PD are presented in Appendix.…”

Section: Mathematical Model Of Doxorubicin Pharmacokinetics (Pk) and supporting

confidence: 83%

“…We believe that the reason for these results is an inter-play between two driving forces. From one side, G-CSF drives the mitotic cells into proliferation [16], where they are more susceptible to doxorubicin [15], justifying delay of G-CSF administration. From the other side, such a delay can compromise efficiency of G-CSF-induced stimulation of myeloid cells leading to delay in neutrophil recovery.…”

Section: Discussionmentioning

confidence: 99%

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Improving Cancer Therapy by Doxorubicin and Granulocyte Colony-Stimulating Factor: Insights from a Computerized Model of Human Granulopoiesis

Vainstein

Ginosar

Shoham

et al. 2006

Math. Model. Nat. Phenom.

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Abstract. Neutropenia is a significant dose-limiting toxicity of cancer chemotherapy, especially in dose-intensified regimens. It is widely treated by injections of Granulocyte ColonyStimulating Factor (G-CSF). However, optimal schedules of G-CSF administration are still not determined. In order to aid in identifying more efficacious and less neutropenic treatment protocols, we studied a detailed physiologically-based computer model of granulopoiesis, as affected by different treatment schedules of doxorubicin and/or Granulocyte ColonyStimulating Factor (G-CSF). We validated the model as evident from accurate prediction of clinical data on human granulopoiesis in healthy individuals and in doxorubicin-treated cancer patients, with or without G-CSF support. Based on our model, we suggest new G-CSF administration regimens. These regimens include reduced G-CSF doses, optimally timed post-chemotherapy. Application of these regimens can lead to minimization of G-CSF side effects, as well as more cost-effective and less myelotoxic protocols. Currently clinical trials are being designed in order to test these new treatment regimens.

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Section: Mathematical Model Of Doxorubicin Pharmacokinetics (Pk) and supporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Improving Cancer Therapy by Doxorubicin and Granulocyte Colony-Stimulating Factor: Insights from a Computerized Model of Human Granulopoiesis

Vainstein

Ginosar

Shoham

et al. 2006

Math. Model. Nat. Phenom.

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“…Unfortunately, this combination results in the destruction of nonmalignant cells including immune cells, which are especially sensitive to radiation. 7,8 Recent reports suggest that RT and immunotherapy might have a synergistic or at least an additive effect against tumors when given sequentially. [9][10][11][12][13] There might also be an advantage of giving the treatments at the same time, provided that tumor-specific T cells can be protected against the effects of RT.…”

Section: Introductionmentioning

confidence: 99%

TLR9 engagement on CD4 T lymphocytes represses γ-radiation–induced apoptosis through activation of checkpoint kinase response elements

Zheng

Asprodites

Keene

et al. 2008

Blood

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T cell-based therapies have much promise in cancer treatment. This approach may be enhanced if used in combination with radiotherapy provided that tumorspecific T cells can be protected against the effects of radiotherapy. Previously, we demonstrated that administration of TLR9 ligand into mice decreased activation-and serum deprivation-induced cell death in T cells. We hypothesized that TLR9 engagement on T lymphocytes decreased apoptosis after cellular stress. We show that TLR9 engagement on murine CD4 T cells reduces ␥-radiation- IntroductionThe development of T cell-based immunotherapy to treat cancer patients has advanced significantly in the last decade due to the identification of multiple tumor antigens and the understanding of the signals that stimulate antitumor T-cell responses. 1 For example, vaccine-based strategies that incorporate tumor antigens (in the form of proteins or peptides) to elicit strong CD4 and CD8 T-cell responses are effective in both the prevention and the treatment of various cancers in preclinical studies. [2][3][4] In cancer patients, infusion of in vitro-activated and expanded tumor-specific T cells has been shown to reduce tumor burden in patients with various types of malignancies. 5 Unfortunately, although T-cell responses are effective against small tumor loads, they are generally ineffective against bulky tumors. 5 One promising strategy is to combine immunotherapy with current anticancer treatments to enhance the antitumor effects.Ionizing radiotherapy (RT) is an important therapy for the treatment of tumors. 6 Generally, RT is administered locally to the tumor site or draining lymph nodes and kills cancer cells by damaging DNA. Radiotherapy is effective at reducing large burdens in some cancers and preventing local recurrence in the case of positive margins. However, RT is rarely curative as a single treatment modality and is therefore often combined with chemotherapy. Unfortunately, this combination results in the destruction of nonmalignant cells including immune cells, which are especially sensitive to radiation. 7,8 Recent reports suggest that RT and immunotherapy might have a synergistic or at least an additive effect against tumors when given sequentially. [9][10][11][12][13] There might also be an advantage of giving the treatments at the same time, provided that tumor-specific T cells can be protected against the effects of RT. 14 The use of toll-like receptor (TLR) agonists as immune adjuvants to improve antitumor T-cell responses has been a subject of intense focus in recent times. Current studies reveal that local injections of TLR agonists can be combined with RT to enhance antitumor T-cell responses; however, these mechanisms remain undefined. [9][10][11][12][13] TLRs are expressed primarily on innate immune cells and activate the immune system by recognizing a range of microbial products, including lipopolysaccharide (TLR4), peptidoglycans and lipopeptides (TLR1 and TLR2), flagellin (TLR5), RNA (TLR3, TLR7, TLR8), and unmethylated "CpG"-DNA (TLR9). 15,16 S...

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“…To evaluate the myelotoxic activity of a drug, the assay of haematopoietic progenitor cell populations appears to be a very valuable test (Marsh, 1976;Lohrmann & Schreml, 1982). As can be seen from previous research Sobrero et al, 1982), although there are no great differences between the effects of different antitumoral drugs on peripheral blood cells and bone marrow cellularity, the differences may become evident when HPC are evaluated.…”

Section: Discussionmentioning

confidence: 99%

Cytotoxic effect of dose and schedule on normal murine hematopoietic progenitor cells following the administration of 4'-deoxydoxorubicin

Pannacciulli¹,

Muzzulini²,

Massa³

et al. 1984

Br J Cancer

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Summary In an experimental setting, 4'-deoxydoxorubicin (4'-deoxy-DX) shows minimal cardiotoxicity as well as the marked antitumoral activity shown by doxorubicin, its parent compound. In this experimental study, the haematologic toxicity of the new anthracycline was investigated by haematopoietic precursor cell (HPC) assays using in vivo (colony-forming units -spleen, CFUS) and in vitro (CFU,-culture) methods with (C57B1 x C3H)F1 mice. Dose-survival curves and time response of HPC in situ following 4'-deoxy-DX administration were determined. In the time-related experiments, the effects of a single dose, an intermittent treatment (Days 0, 2, and 5) and a prolonged biweekly administration were studied. All dose-survival curves were exponential, with statistically significant differences between the effects on the various cell classes. CFUC appeared more sensitive than CFU,. In time-related experiments, 4'-deoxy-DX toxicity for HPC seemed to be relatively mild. However, CFU, sensitivity was again high in comparison with other populations assayed. In long-term administration, the 4-deoxy-DX effects on the haematopoietic system were also rather slight.

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Cytotoxic Drugs and the Granulopoietic System

Cited by 37 publications

References 0 publications

Improving Cancer Therapy by Doxorubicin and Granulocyte Colony-Stimulating Factor: Insights from a Computerized Model of Human Granulopoiesis

Improving Cancer Therapy by Doxorubicin and Granulocyte Colony-Stimulating Factor: Insights from a Computerized Model of Human Granulopoiesis

TLR9 engagement on CD4 T lymphocytes represses γ-radiation–induced apoptosis through activation of checkpoint kinase response elements

Cytotoxic effect of dose and schedule on normal murine hematopoietic progenitor cells following the administration of 4'-deoxydoxorubicin

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